Although neuropeptides are well known to exert a wide range of pro-inflammatory effects after administration of pharmacological dosages into normal tissue, relatively little is known about their physiologic functions in regulating inflammation and healing. The applicants have developed a technique for collecting inflammatory mediators, including neuropeptides, by implanting microdialysis probes into surgical wounds of awake, post-oral surgery patients or in anesthetized rats following tissue injury. Ongoing studies performed by the applicants show that physiologic levels of immunoreactive substance P (iSP) are released into the surgical wounds of dental patients, and that bradykinin, prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) all mediate, via receptor-dependent mechanisms, increases in surgical wounds of iSP levels. In this competing renewal application, the proposed multidisciplinary studies are designed to identify physiologic systems regulating wound levels of iSP in humans, determine whether efferent dorsal root reflexes contribute to the initiation of neurogenic inflammation in human and rat surgical wounds, and to evaluate whether elevated iSP concentrations, detected in surgical wounds, mediate the development of surgery-induced neurogenic inflammation and wound healing. The applicants propose both clinical and animal studies. Clinical Studies: 1. To determine the peripheral effects of drugs that modulate neurogenic inflammation (capsaicin) on altering tissue levels of i-SP and an index of neurogenic inflammation (local hyperthermia) in the surgical wounds of awake patients following extraction of impacted mandibular third molars. 2. To determine the contribution of efferent neuronal outflow (e.g., dorsal root reflexes) on the initiation of neurogenic inflammation in the surgical wounds of awake patients following extraction of impacted mandibular third molars. Animal Studies: 1. To determine the magnitude of the neurogenic component of inflammation observed following surgical extraction of teeth in anesthetized rats. 2. To determine whether endogenous substance P (SP) contributes to the neurogenic component of inflammation observed following surgical extraction of teeth in anesthetized rats. 3. To determine the magnitude of the neurogenic component of wound healing observed following surgical extraction of teeth in anesthetized rats. 4. To determine whether endogenous SP contributes to wound healing observed following surgical extraction of teeth in anesthetized rats. Collectively, the proposed studies will determine the efferent regulation of iSP levels in surgical wounds of humans, and, in a parallel rat model, determine the role of SP in post-surgical inflammation and wound healing. This knowledge may well provide a physiological basis for improved surgical outcomes.